2 Disclosure I have no actual or potential conflict of interest in relation to this activity. I do plan on discussing unlabeled or investigational uses of a commercial product. 2

3 Goal: To describe the risks associated with the concomitant use of opiate and benzodiazepine medications. Objectives: List the pharmacodynamic interactions between the opiate and benzodiazepine (BZD) class of drugs, Identify the physiological presentation of benzodiazepine and opiate combination use, Describe possible benefit of this combination of medications, and Explain when this combination of medication classes presents a risk to the patient. 3

4 Frequency of concomitant use In patients abusing opiates rates are nearly 75% concomitant use. 72% of methadone users who were coprescribed BZDs found the BZD enhanced the opiate effect. More commonly seen in in-treatment patients compared to untreated heroin users. In methadone maintenance treatment pts rates are over 50%. Buprenorphine treated pts have similar rates. Some pts are legally prescribed BZDs but most are using illegally. Also results in worse w/d syndrome. In chronic pain approximately 33% opiate and BZD coprescribed. Backmund M. J Addict Dis Jones JD. Drug Alc Dep Manchikanti L. Pain Physician

5 Increase in prescribing Primary care clinics are increasing BZD and opiate prescriptions, both monotherapy and as combination therapy. 12% increase in coprescribing. Same trend is also seen in ED rxs. 6.4% inc in coprescribing. Often started from 2 separate prescribers then continued by new prescriber. Kao M. Poster presentation AAPM 30 th Annual Meeting

15 Assessment Question Which of the following is true regarding pharmacokinetic interactions with opiates and benzodiazepines? A. Diazepam has shown to increase methadone and buprenorphine in some studies but not all. B. Lorazepam consistently increases blood levels of oxycodone. C. Pharmacokinetic interactions may exist but are not likely the major reason for risks associated with combination therapy. D. A and C only. 15

16 Answer Which of the following is true regarding pharmacokinetic interactions with opiates and benzodiazepines? A. Diazepam has shown to increase methadone and buprenorphine in some studies but not all. B. Lorazepam consistently increases blood levels of oxycodone. C. Pharmacokinetic interactions may exist but are not likely the major reason for risks associated with combination therapy. D. A and C only. 16

20 Bluelight.org I took 30mg hydrocodone and need help falling asleep. Took 2mg etizolam 10 minutes ago and plan on feeling good for a little while then passing out. Is this combination really that bad?

21 Bluelight.org - responses I died for almost a minute on the combination. I really blacked out and woke up from a dream realizing I just smashed my car. I did 8mg of Xanax and 40mg Opana no problem. I did 13mg of Xanax and 40mg Opana and woke up with a doctor staring down at me amazed I was still alive. I have overdosed and actually died due to benzos and opiates. 21

22 Bluelight.org - responses If you know your limits it can go fine. If you are tolerant to opiates and benzos, and dose accordingly, you are not guaranteed death. Plenty of us combine the two. Even now I don t leave home without washing 4mg of clonazepam with methadone syrup. I usually find the heroin in the UK so weak I won t bother getting heroin unless I got some benzos. 22

27 Benefits of adding opiates and BZDs Preoperatively Hypnotic and analgesic Agitation in the ICU Ventilated patients Few published reports of using both together for maintenance purposes. Anxiety guidelines rarely recommend the use of daily BZDs. Contrarily, chronic pain guidelines do suggest that patients may require daily opiate therapy. Most warn against combo use. 27

28 Guideline recommendations Generalized Anxiety Disorder British Association of Psychopharmacology (2014) Acute phase Start SSRIs, TCAs and add BZD if necessary Prophylaxis SSRIs, SNRIs, buspirone, pregabalin NICE (2007) SSRIs for 12 weeks then switch to another for at least 6 mos. Benzos for no more than 4 weeks Venlafaxine second line (dose 75mg or less)

29 Guideline recommendations Generalized Anxiety Disorder Canadian Psychiatric Association (2006) SSRIs and venlafaxine. Second line Buspirone, pregabalin, imipramine Bupropion XL Benzos in the acute phase. Have shown long term benefit in some studies.

30 Assessment Question LJ is a 35 yo female who is admittedly uses oxycodone recreationally. She has been diagnosed with generalized anxiety disorder (GAD) and is expecting to be prescribed diazepam. Which of the following is the most appropriate treatment for her GAD? A. Diazepam is the most appropriate treatment. B. Initiate escitalopram (an SSRI), low dose and taper up as needed. C. Initiate lorazepam low dose and taper up as necessary. D. Prescribe the oxycodone on a scheduled basis. 30

31 Answer LJ is a 35 yo female who is admittedly uses oxycodone recreationally. She has been diagnosed with generalized anxiety disorder (GAD) and is expecting to be prescribed diazepam. Which of the following is the most appropriate treatment for her GAD? A. Diazepam is the most appropriate treatment. B. Initiate escitalopram (an SSRI), low dose and taper up as needed. C. Initiate lorazepam low dose and taper up as necessary. D. Prescribe the oxycodone on a scheduled basis. 31

33 Guideline recommendations Panic Disorder American Psychiatric Association (APA-2008) SSRIs and SNRIs TCAs BZDs for the first 4-6 weeks of treatment only. Canadian Psychiatric Association (2006) First line SSRIs and venlafaxine Second line TCAs BZDs for acute treatment only

36 conclusion Concomitant use has little data for support in maintenance therapy. Frequent concomitant use from legal prescriptions and obtained illegally. Kinetic interactions exist but unlikely to have a dramatic impact. Watch for CYP 450 3A4 combos Dynamic interaction results in substantial reduction in respiratory drive. Combination often sought after due to dynamic interaction of a subjective experience of more intense euphoria. Should place more vigilance on concomitant use to verify benefit is worth the risk. 36

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